CN107427507B

CN107427507B - Therapeutic agent for respiratory infection

Info

Publication number: CN107427507B
Application number: CN201680015197.3A
Authority: CN
Inventors: 久米广太; 吉田尚生; 安藤裕崇; 田中裕太
Original assignee: Kyorin Pharmaceutical Co Ltd
Current assignee: Xinglin Holding Co; Kyorin Pharmaceutical Co Ltd
Priority date: 2015-03-13
Filing date: 2016-03-11
Publication date: 2021-12-17
Anticipated expiration: 2036-03-11
Also published as: EA201791995A1; AU2016234411A1; CN113975277A; CN107427507A; SG11201706951XA; US20190076421A1; BR112017019205A2; SG10201908007UA; KR20170123695A; JPWO2016148066A1; AU2016234411B2; US10918634B2; MY191848A; AU2016234411C1; IL253878A0; EP3269369A1; CA2978261A1; EP3269369A4; US20180042918A1; JP6077725B1

Abstract

[ problem ] the present invention relates to a safer and more effective therapeutic agent for respiratory organ infection. [ solution ] A therapeutic agent for respiratory organ infection, which contains 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof as an active ingredient.

Description

Therapeutic agent for respiratory infection

Technical Field

The present invention relates to a therapeutic agent for respiratory organ infection.

Background

Since the development of norfloxacin, quinolone carboxylic acid-based antibacterial agents known as new quinolones have been developed worldwide. Currently, many new quinolone-based antibacterial agents are widely used as infection therapeutics.

On the other hand, a quinolone carboxylic acid derivative represented by general formula (1) is disclosed by the present applicant (patent document 1).

[ chemical formula 1]

In the formula (1), R¹Is an alkyl group having 1 to 6 carbon atoms, of which 1 or 2 or more hydrogen atoms may be substituted with 1 or 2 or more halogen atoms; a cycloalkyl group having 3 to 6 carbon atoms, which may be substituted with 1 or 2 or more halogen atoms; or aryl or heteroaryl, which may be substituted by 1 or 2 or more substituents which may be the same or different and are selected from: a halogen atom and an amino group; r²Is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or a pharmaceutically acceptable cation; r³Is a hydrogen atom, a halogen atom, a hydroxyl group, an amino group or an alkyl group having 1 to 3 carbon atoms; r⁴Is a hydrogen atom or a halogen atom; r⁵Is a fluorine atom; r⁶Is a hydrogen atom or a fluorine atom; and a is a nitrogen atom or ═ C-X (wherein X is a hydrogen atom, a halogen atom, an amino group, a cyano group, or an alkyl group or an alkoxy group having 1 to 3 carbon atoms and which may be substituted with 1 or 2 or more halogen atoms.

Patent document 1 also discloses 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid as an example of a quinolone carboxylic acid derivative. Its hydrochloride is disclosed in patent document 2.

Reference list

Patent document

Patent document 1 WO2005/026147

Patent document 2 WO2013/069297

Summary of The Invention

Technical problem

The object of the present invention is to provide a novel therapeutic agent for respiratory infection.

Means for solving the problems

The present inventors have studied a safer and more effective therapeutic agent for respiratory organ infection.

As a result, the inventors have found that, among quinolone carboxylic acid derivatives represented by general formula (1), 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid and pharmaceutically acceptable salts thereof (particularly hydrochloride thereof) have a remarkably high tissue distribution rate (packet migration rate) into respiratory organs (particularly lungs) and rapidly distribute into respiratory organs after administration, and thus are extremely useful as a therapeutic agent for respiratory organ infection. Thus, the present invention has been completed.

The summary of the invention is as follows:

[1] a therapeutic agent for respiratory organ infection, which comprises 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof as an active ingredient.

[2] The therapeutic agent according to [1], wherein the respiratory organ infection therapeutic agent is a respiratory organ infection therapeutic agent for humans.

[3] The therapeutic agent according to [1] or [2], wherein the respiratory organ infection is one or two or more infections selected from the group consisting of: pharyngitis, laryngitis, tonsillitis, acute bronchitis, pneumonia and secondary infection of chronic respiratory diseases.

[4] The therapeutic agent according to any one of [1] to [3], wherein pathogenic bacteria causing the respiratory organ infection are one or two or more bacteria selected from the group consisting of: bacteria belonging to the genus Staphylococcus, bacteria belonging to the genus Streptococcus, Moraxella catarrhalis, bacteria belonging to the genus Klebsiella, Haemophilus influenzae and Escherichia coli.

[5] The therapeutic agent according to any one of [1] to [4], wherein the pathogenic bacteria causing the respiratory organ infection are one or two or more bacteria belonging to any one of Streptococcus and Staphylococcus.

[6] The therapeutic agent according to any one of [1] to [5], wherein pathogenic bacteria causing the respiratory organ infection have drug resistance.

[7] The therapeutic agent according to any one of [1] to [6], wherein the daily dose of 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof is 10mg to 250 mg.

[8] A therapeutic agent for an infection, the infection being one or two or more selected from the group consisting of: pharyngitis, laryngitis, tonsillitis, acute bronchitis, pneumonia, secondary infection of chronic respiratory diseases, sinusitis and otitis media, wherein the pathogenic bacterium is Streptococcus pneumoniae, and the therapeutic agent comprises 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof as an active ingredient.

[9] A method for treating a respiratory organ infection comprising administering to a subject in need thereof 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof in an amount effective to treat the respiratory organ infection.

[10] The method of [9], wherein the subject is a human.

[11] The method according to [9] or [10], wherein the respiratory organ infection is one or two or more infections selected from the group consisting of: pharyngitis, laryngitis, tonsillitis, acute bronchitis, pneumonia and secondary infection of chronic respiratory diseases.

[12] The method according to any one of [9] to [11], wherein the pathogenic bacteria causing the respiratory organ infection are one or two or more bacteria selected from the group consisting of: bacteria belonging to the genus Staphylococcus, bacteria belonging to the genus Streptococcus, Moraxella catarrhalis, bacteria belonging to the genus Klebsiella, Haemophilus influenzae and Escherichia coli.

[13] The method according to any one of [9] to [12], wherein the pathogenic bacteria causing the respiratory organ infection are one or two or more bacteria belonging to any one of Streptococcus and Staphylococcus.

[14] The method according to any one of [9] to [13], wherein a pathogenic bacterium causing the respiratory organ infection has drug resistance.

[15] The method according to any one of [9] to [14], wherein the daily dose of 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof is 10mg to 250 mg.

[16]7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid, or a pharmaceutically acceptable salt thereof, for use in the treatment of a respiratory organ infection.

[17] The compound for use in the treatment of a respiratory organ infection according to [16], wherein the respiratory organ infection is a human respiratory organ infection.

[18] The compound for use in the treatment of a respiratory organ infection according to [16] or [17], wherein the respiratory organ infection is one or two or more infections selected from the group consisting of: pharyngitis, laryngitis, tonsillitis, acute bronchitis, pneumonia and secondary infection of chronic respiratory diseases.

[19] The compound for use in the treatment of a respiratory organ infection according to any one of [16] to [18], wherein pathogenic bacteria causing the respiratory organ infection are one or two or more bacteria selected from the group consisting of: bacteria belonging to the genus Staphylococcus, bacteria belonging to the genus Streptococcus, Moraxella catarrhalis, bacteria belonging to the genus Klebsiella, Haemophilus influenzae and Escherichia coli.

[20] The compound for use in the treatment of a respiratory organ infection according to any one of [16] to [19], wherein a pathogenic bacterium causing the respiratory organ infection is one or two or more bacteria belonging to any one of Streptococcus and Staphylococcus.

[21] The compound for use in the treatment of a respiratory organ infection according to any one of [16] to [20], wherein a pathogenic bacterium causing the respiratory organ infection has drug resistance.

[22] The compound for use in the treatment of a respiratory organ infection according to any one of [16] to [21], wherein the daily dose of 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof is 10mg to 250 mg.

[23] Use of 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a respiratory organ infection.

[24] The use of [23], wherein the respiratory organ infection is a human respiratory organ infection.

[25] The use according to [22] or [24], wherein the respiratory organ infection is one or two or more infections selected from the group consisting of: pharyngitis, laryngitis, tonsillitis, acute bronchitis, pneumonia and secondary infection of chronic respiratory diseases.

[26] The use according to any one of [23] to [25], wherein the pathogenic bacteria causing the respiratory organ infection are one or two or more bacteria selected from the group consisting of: bacteria belonging to the genus Staphylococcus, bacteria belonging to the genus Streptococcus, Moraxella catarrhalis, bacteria belonging to the genus Klebsiella, Haemophilus influenzae and Escherichia coli.

[27] The use according to any one of [23] to [26], wherein the pathogenic bacteria causing the respiratory organ infection are one or two or more bacteria belonging to any one of Streptococcus and Staphylococcus.

[28] The use according to any one of [23] to [27], wherein a pathogenic bacterium causing the respiratory organ infection has drug resistance.

[29] The use according to any one of [23] to [28], wherein the daily dose of 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof is 10mg to 250 mg.

[30] A method for treating an infection, said infection being one or two or more selected from the group consisting of: pharyngitis, laryngitis, tonsillitis, acute bronchitis, pneumonia, secondary infections of chronic respiratory diseases, sinusitis and otitis media, wherein the pathogenic bacterium is streptococcus pneumoniae, said method comprising administering to a subject in need thereof 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof in an amount effective to treat respiratory infections.

[31]7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid, or a pharmaceutically acceptable salt thereof, for use in treating an infection selected from one or two or more of: pharyngitis, laryngitis, tonsillitis, acute bronchitis, pneumonia, secondary infection of chronic respiratory diseases, sinusitis and otitis media, wherein the pathogenic bacteria is Streptococcus pneumoniae.

[32] Use of 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an infection selected from one or two or more of: pharyngitis, laryngitis, tonsillitis, acute bronchitis, pneumonia, secondary infection of chronic respiratory diseases, sinusitis and otitis media, and wherein the pathogenic bacterium is Streptococcus pneumoniae.

[33] The therapeutic agent according to [8], wherein the daily dose of 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof is 10mg to 250 mg.

[34] The therapeutic agent according to [1], wherein the daily dose of 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof is 75mg or twice this amount.

[35] A therapeutic agent for one or two or more infections selected from: pharyngitis, laryngitis, tonsillitis, acute bronchitis, pneumonia, secondary infections of chronic respiratory diseases, sinusitis and otitis media, said therapeutic agent comprising 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof, wherein the daily dose of said compound is 75mg or twice this amount.

[36] The therapeutic agent according to [35], wherein the pathogenic bacterium causing the infection is Streptococcus pneumoniae.

[37] The therapeutic agent according to [1], wherein the maximum plasma concentration of 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof is 3 μ g/mL or less after the therapeutic agent is administered to a human having a respiratory organ infection.

[38] The therapeutic agent according to [1], wherein the maximum plasma concentration of 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof is 0.5. mu.g/mL-1.5. mu.g/mL after the therapeutic agent is administered to a human having a respiratory organ infection.

[39] The therapeutic agent according to [1], wherein the maximum plasma concentration of 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof is 0.7. mu.g/mL-1.2. mu.g/mL after the therapeutic agent is administered to a human having a respiratory organ infection.

[40] The therapeutic agent according to [37], wherein the daily dose of 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof is 75mg or twice this amount.

[41] The therapeutic agent according to [38] or [39], wherein the daily dose of 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof is 75 mg.

[42] An infection therapeutic agent comprising 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof, wherein the tissue distribution rate of the compound into the alveolar epithelial lining fluid 1 hour after administration to a human is 10 or more.

[43] An infection therapeutic agent comprising 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof, wherein the tissue distribution rate of the compound into the alveolar epithelial lining fluid 1 hour after administration to a human is 10 to 50.

[44] An infection therapeutic agent comprising 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof, wherein the tissue distribution rate of the compound into the alveolar epithelial lining fluid 1 hour after administration to a human is 15 to 40.

Advantageous effects of the invention

The present invention can provide a technique relating to a novel therapeutic agent for respiratory organ infection.

Brief Description of Drawings

FIG. 1 is a graph showing the number of bacteria in the lungs of mice after subcutaneous administration of the drug in test example 6.

Fig. 2 is a graph showing the number of bacteria in the lungs of mice after oral administration of the drug in test example 6.

Description of the embodiments

Hereinafter, one of the embodiments of the present invention will be described in detail.

The therapeutic agent of the present embodiment relates to a respiratory organ infection therapeutic agent, for example, useful for treating respiratory organ infection in humans.

Respiratory organ infection means infection caused at any part of the respiratory organ.

Respiratory organs refer collectively to the organs involved in breathing and mean the organs from the nasal vestibule, through the nasal cavity, pharynx, larynx, trachea, bronchi and bronchioles to the alveoli.

Examples of respiratory organ infections involving the therapeutic agent of the present embodiment may include one or two or more respiratory organ infections selected from the group consisting of: cold, pharyngitis, laryngitis, epiglottitis, tonsillitis (including peritonsillar inflammation and peritonsillar abscess), bronchitis (including acute bronchitis, chronic bronchitis and diffuse panbronchiolitis), pneumonia, secondary infection of chronic respiratory diseases and bronchiectasis.

Among these infections, in order to treat one or two or more respiratory organ infections selected from pharyngitis, laryngitis, tonsillitis, acute bronchitis, pneumonia and secondary infections of chronic respiratory organ diseases, it is preferable to use the therapeutic agent of the present embodiment. In a more preferred embodiment, the target disease of the therapeutic agent may be one or two or more respiratory organ infections selected from: acute bronchitis, pneumonia, and secondary infection of chronic respiratory diseases, because the compound according to the present embodiment can be rapidly transferred to the site where symptoms occur, to achieve more effective treatment.

Pathogenic bacteria causing respiratory organ infection, which is a target disease of the therapeutic agent of the present embodiment, are, for example, one or two or more kinds of bacteria selected from the group consisting of: bacteria belonging to the genus Staphylococcus, bacteria belonging to the genus Streptococcus, Moraxella catarrhalis (Hansenula catarrhalis), bacteria belonging to the genus Klebsiella, bacteria belonging to the genus Enterobacter, Haemophilus influenzae, bacteria belonging to the genus enterococcus, Escherichia coli, Pseudomonas aeruginosa, Legionella, Chlamydia, Mycoplasma, Coxiella beijerinckii, Bordetella pertussis, and anaerobic bacteria.

The pathogenic bacteria against which the therapeutic agent of the present embodiment is used are more preferably one or two or more bacteria selected from the group consisting of: bacteria belonging to the genus Staphylococcus, bacteria belonging to the genus Streptococcus, Moraxella catarrhalis, bacteria belonging to the genus Klebsiella, bacteria belonging to the genus Enterobacter, Haemophilus influenzae, Legionella pneumophila, Chlamydophila pneumoniae, Mycoplasma pneumoniae, and Escherichia coli, and further preferably one or two or more bacteria selected from the group consisting of: bacteria belonging to the genus Staphylococcus, bacteria belonging to the genus Streptococcus, Moraxella catarrhalis, bacteria belonging to the genus Klebsiella, Haemophilus influenzae, and Escherichia coli, and one or two or more kinds of bacteria belonging to any of the genera Streptococcus and Staphylococcus are particularly preferred.

Examples of pathogenic bacteria belonging to the genus Streptococcus may include pneumococcus, Streptococcus pyogenes, hemolytic streptococci, and Streptococcus sanguis. Among these, the pathogenic bacterium targeted with the therapeutic agent of the present embodiment is preferably streptococcus pneumoniae. Examples of pathogenic bacteria belonging to the genus Staphylococcus may include Staphylococcus aureus and Staphylococcus epidermidis. Among these, the pathogenic bacterium against which the therapeutic agent of the present embodiment is used is preferably staphylococcus aureus. Thus, the therapeutic agent of this embodiment may be used to treat one or two or more respiratory organ infections selected from acute bronchitis, pneumonia and secondary infections of chronic respiratory organ disease, and wherein the pathogenic bacteria are streptococcus pneumoniae and/or staphylococcus aureus.

Herein, pathogenic bacteria means a concept including bacteria that have acquired resistance to a drug. Drug resistance refers to a phenomenon in which an organism has resistance to a drug and the drug is ineffective or unlikely to be effective. Examples of resistance may include resistance to penicillin, resistance to cephalosporins, resistance to carbapenem, resistance to aminoglycosides, resistance to macrolides, resistance to lincomycin, resistance to sulfamethoxazole (トリメトプリム - スルファ), resistance to tetracycline, resistance to metronidazole, resistance to glycopeptides, resistance to oxazolidinones, resistance to daptomycin, and resistance to quinolones.

Examples of bacteria that have acquired resistance to drugs may include penicillin-resistant bacteria, such as penicillin-resistant streptococcus pneumoniae (PRSP); methicillin-resistant bacteria, such as methicillin-resistant staphylococcus aureus (MRSA) and methicillin-resistant staphylococcus epidermidis (MRSE); vancomycin-resistant bacteria, such as vancomycin-resistant enterococci (VRE); macrolide-resistant bacteria, such as macrolide-resistant streptococcus pneumoniae; and quinolone resistant bacteria, such as quinolone resistant streptococcus pneumoniae.

The disease to be treated with the therapeutic agent of the present embodiment may be any of respiratory organ infections in which pathogenic bacteria are non-drug resistant bacteria and respiratory organ infections in which pathogenic bacteria are bacteria that have acquired drug resistance, and is not particularly limited. On the other hand, since the therapeutic agent of the present embodiment also exhibits an excellent therapeutic effect on respiratory organ infections in which pathogenic bacteria are bacteria that have acquired resistance to drugs, pathogenic bacteria that cause target diseases of the therapeutic agent of the present embodiment may preferably be quinolone-resistant bacteria, and more preferably quinolone-resistant streptococcus pneumoniae and/or quinolone-resistant staphylococcus aureus. Thus, the therapeutic agent of the present embodiment may be used to treat one or two or more respiratory organ infections selected from acute bronchitis, pneumonia and secondary infections of chronic respiratory organ disease, and wherein the pathogenic bacteria are quinolone-resistant streptococcus pneumoniae and/or quinolone-resistant staphylococcus aureus.

The therapeutic agent of this embodiment may consist of 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid alone or a pharmaceutically acceptable salt thereof. The therapeutic agent of the present embodiment may be a pharmaceutical composition containing 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof, and a further compound serving as an active ingredient, and/or a pharmaceutically acceptable additive.

The pharmaceutical composition may contain one or more compounds as further compounds acting as active ingredients and/or as pharmaceutically acceptable additives. The pharmaceutical composition may be prepared, for example, by: mixing 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof with one or more of a compound or an additive serving as an active ingredient.

Examples of pharmaceutically acceptable additives contained with 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof may include excipients, lubricants, binders, disintegrants, stabilizers, flavors and diluents. These additives are not particularly limited as long as they can be used for preparing pharmaceutical preparations, and for example, additives listed in "medicament supplement science (collapsible medicine, (2007) in japan)" can be appropriately used.

The therapeutic agent of the present embodiment can be administered to a subject (e.g., a human) by an administration route which is very conventionally known as a pharmaceutical form. For example, the therapeutic agent may be administered orally or non-orally in the form of a formulation such as powder, tablet, capsule, fine granule, syrup, injection, ophthalmic liquid, aqueous nasal drop, aqueous ear drop or inhalation liquid. Specifically, the therapeutic agent of the present embodiment can be prepared in the form as exemplified above, for example, by mixing a physiologically acceptable carrier, excipient, binder, diluent, and the like with the active ingredient.

In order to reduce side effects, form a small-sized preparation that can be easily administered, and prevent the development of drug-resistant bacteria, the daily dose of 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof is preferably 10mg to 250mg, more preferably 20mg to 200mg, further preferably 30mg to 160mg, still more preferably 40mg to 100mg, still more preferably 50mg to 90mg, and particularly preferably 60mg to 80 mg. The daily dose of the therapeutic agent may be administered once or in divided doses two to three times. Preferably, the therapeutic agent is administered once daily. When the effect is insufficient, the therapeutic agent may be used in an amount twice the daily dose.

To quickly reach the target blood level, loading administration may be performed. Loading administration means a dosing design in which the daily dose or the number of daily administrations in the early stage of administration is increased to reach the target blood level quickly. The early stage of administration means from day 1 to day 3 of the initial administration, preferably from day 1 to day 2, more preferably day 1 of the initial administration. As an increased daily dose, it is preferred to use an amount of twice the daily dose.

When a loading administration is carried out, it is preferable to use an amount of twice the daily dose on the 1 st day of the initial administration.

The pharmaceutically acceptable salt of 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid is not particularly limited as long as it is a pharmacologically acceptable salt. Examples thereof may include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; salts with organic acids such as maleic acid, fumaric acid, succinic acid, malic acid, malonic acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, acetic acid, trifluoroacetic acid and tartaric acid; and salts with metals such as sodium, potassium, magnesium, calcium, aluminum, cesium, chromium, cobalt, copper, iron, zinc, platinum, and silver. In particular, the hydrochloride is particularly preferable from the viewpoint of stability and distribution rate to the lung.

7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof can be prepared, for example, according to the method described in patent document 1 or 2.

Accordingly, the present embodiments may provide techniques related to novel treatments of respiratory organ infections.

7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid and its pharmaceutically acceptable salts (and especially its hydrochloride salt) have a significantly high tissue distribution rate into the respiratory organ, especially the lungs, and distribute rapidly into the respiratory organ after administration. The tissue distribution rate into the human respiratory organ is more excellent than that of other quinolone compounds.

For example, the maximum plasma concentration of 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof may be 3 μ g/mL or less after administration of the therapeutic agent according to this embodiment to a human suffering from a respiratory organ infection. In this case, the daily dose of 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof may be 75mg or twice that amount.

In a preferred aspect, the maximum plasma concentration of 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid, or a pharmaceutically acceptable salt thereof, can be from 0.5 μ g/mL to 1.5 μ g/mL, and in a more preferred aspect, the maximum plasma concentration can be from 0.7 μ g/mL to 1.2 μ g/mL, following administration of a therapeutic agent according to this embodiment to a human suffering from a respiratory organ infection. In this case, the daily dose of 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof may be 75 mg.

Therefore, a therapeutic agent whose dose is smaller than that of another drug can be expected to be effective against a lesion in lung tissue or the like. Therefore, it is expected to reduce side effects, form a small-sized formulation that can be easily administered, prevent the development of drug-resistant bacteria, and the like.

In addition, the therapeutic agent of the present embodiment also exhibits an excellent therapeutic effect on respiratory organ infections in which pathogenic bacteria are bacteria that have acquired resistance (e.g., quinolone-resistant bacteria).

In addition, the therapeutic agent of the present embodiment has the following properties: the development frequency of resistant bacteria is lower than that of resistant bacteria in other quinolone compounds.

Therefore, the present embodiment can provide a therapeutic agent for respiratory organ infection, which has excellent effectiveness and safety.

Examples

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to the scope of the present invention by (limited to) these examples.

[ reference example 1-1] ¹⁴ ₁6, 7-difluoro-1- (2-fluoroethyl) -8-methoxy-1, 4-dihydro-4-oxo [2-C]Quinoline- 3-Carboxylic acid ethyl ester (Compound A-1)

[ chemical formula 2]

Under a nitrogen atmosphere, ethyl 3- (2,4, 5-trifluoro-3-methoxy) phenyl-3-oxopropanoate (1397.4mg,5.06mmol), acetic anhydride (13.4mL) and n- (2,4, 5-trifluoro-3-methoxy) benzene¹⁴C]A mixture (reaction solution) of triethyl formate (293mCi, 851. mu.L, 758mg,5.05mmol, density: 0.891g/mL) was heated and refluxed for 1 hour. The reaction solution was cooled to room temperature, toluene (17mL) was added to the reaction solution, and the obtained mixture was concentrated under reduced pressure using a rotary evaporator. Toluene (17mL) was added to the residue, and the mixture was concentrated under reduced pressure using a rotary evaporator. This operation was repeated 4 times to obtain a yellow oily product.

To the residue obtained as an oily product were added dimethyl sulfoxide (13.4mL), 2-fluoroethylamine hydrochloride (1259.84mg,12.7mmol) and potassium carbonate (1745.4mg,12.6mmol), to obtain a reaction liquid. The reaction solution was stirred at 47 ℃ for 3 hours under nitrogen atmosphere. Potassium carbonate (1752.9mg,12.7mmol) was added to the reaction solution, and the mixture was stirred at 78 ℃ for 1 hour, and then stirred at room temperature overnight to obtain a reaction solution. To the reaction solution were added water (50.5mL) and acetone (8.4mL), and the mixture was stirred at room temperature for 20 minutes and then at 0 ℃ for 30 minutes to obtain a precipitate. The precipitate was collected by filtration and washed twice with a mixture of water and acetone (5mL) (water: acetone ═ 6: 1). The resulting solid was dried under reduced pressure to obtain 1286.8mg of a crude product.

To the crude product obtained, ethanol (24mL) was added. The mixture was heated and refluxed under nitrogen atmosphere until the solid was completely dissolved. The mixed solution was gradually cooled to room temperature, and water (5mL) was added. Then, the mixture was stirred at room temperature for 20 minutes and at 10 to 15 ℃ for 30 minutes to obtain a precipitate. The precipitate was collected by filtration and washed twice with ethanol (1.6 mL). The solid was dried at 40 ℃ until the mass was constant.

Ethanol (21.8mL) was added to the solid obtained and the mixture was heated and refluxed under nitrogen atmosphere until the solid was completely dissolved. The obtained solution is gradually cooled to room temperature and stirred for 30 minutes at 10-15 ℃ to obtain a precipitate. The precipitate was collected by filtration, washed twice with ethanol (1.4mL), and dried under reduced pressure at 35-40 ℃ for 1 hour. This operation was repeated two or more times to obtain 878.97mg (2.65mmol,153.8mCi, yield: 53%)¹⁴C-6, 7-difluoro-1- (2-fluoroethyl) -8-methoxy-1, 4-dihydro-4-oxo [2-¹⁴C₁]Quinoline-3-carboxylic acid ethyl ester (Compound A-1).

[ reference examples 1 to 2]6, 7-difluoro-1- (2-fluoroethyl) -8-methoxy-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid Ethyl ester (Compound A-2)

[ chemical formula 3]

Use triethyl orthoformate in place of orthodox [2]¹⁴C]Triethyl formate and the same operation as in referential example 1-1 was carried out. Thus, ethyl 6, 7-difluoro-1- (2-fluoroethyl) -8-methoxy-1, 4-dihydro-4-oxoquinoline-3-carboxylate (compound A-2) was obtained.

[ reference example 2]Bis (acetoxy-O) - [6, 7-difluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-di ¹⁴ ₁ ³ ⁴Hydrogen 2-C]Quinoline-3-carboxylic acid radical-O, O]Boron (Compound B)

[ chemical formula 4]

A mixture (reaction solution) of boric acid (954mg,15.4mmol), acetic anhydride (8.4mL), and zinc chloride (7.1mg,0.05mmol) was stirred at room temperature under a nitrogen atmosphere for 10 minutes. To the reaction mixture were added compound A-1(878mg,2.65mmol) and compound A-2(400mg,1.22 mmol). The reaction solution was stirred at 55 ℃ for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to 30 ℃ and acetone (6.3mL) was added to the reaction mixture. The resulting mixture containing acetone was added to a mixed solution of water (44.5mL) and an aqueous ammonia solution (28% w/w) (7.7mL) at 0 ℃ with stirring. The mixture was stirred at 0 ℃ for 30 minutes to precipitate a white solid. The white solid was collected by filtration and washed twice with water (1 mL). The resulting solid was dried under reduced pressure at 65 ℃ to yield 1549.6mg (143.2mCi) of crude product.

To the crude product obtained was added acetone (6.3 mL). Under nitrogen atmosphere, the mixture was heated and refluxed until the solid was completely dissolved. The mixture was gradually cooled to room temperature, and isopropyl ether (6.3mL) was added to the mixture. Thereafter, the mixture was stirred at room temperature for 15 minutes and at 10 ℃ for 30 minutes, to obtain a precipitate. The precipitate was collected by filtration and washed twice with a mixture (2mL) of acetone and diisopropyl ether (1: 2). The precipitate was dried under reduced pressure at 65 ℃ to obtain 1532.82mg (3.56mmol) of Compound B (yield: 92%).

[ reference example 3]7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl]-6-fluoro-1- (2-) ¹⁴ ₁Fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydro [2-C]Quinoline-3-carboxylic acid hydrochloride (Compound C)

[ chemical formula 5]

A mixture (reaction solution) of (3R,4S) -3-cyclopropylaminomethyl-4-fluoropyrrolidine (880mg,3.81mol), triethylamine (2.9mL,2.1g,20.8mmol) and dimethylsulfoxide (14.9mL) was stirred at room temperature under a nitrogen atmosphere for 10 minutes. To the reaction solution was added compound B (1489.2mg,3.46mmol) prepared in reference example 2, and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. To the reaction solution were added ethyl acetate (30mL), water (30mL) and a 2mol/L aqueous solution of sodium hydroxide (3.0mL,6.00mmol), and the mixture was stirred at room temperature for 5 minutes and separated into an aqueous layer and an organic layer. The aqueous layer was washed twice with ethyl acetate (30mL), and the combined organic layers were washed with water (30mL) and saturated brine (30mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.

To the residue were added 2-propanol (30mL) and 2mol/L hydrochloric acid (7.7mL,15.4mmol) to obtain a reaction solution. The reaction solution was stirred at room temperature for 30 minutes. 2-propanol (14.8mL) was added to the reaction solution, and the reaction solution was stirred at 60 ℃ for 45 minutes. The reaction solution was cooled to room temperature and stirred at 0 ℃ for 30 minutes to obtain a precipitate. The precipitate was collected by filtration and washed three times with 2-propanol (1.5 mL). The resultant was dried under reduced pressure to obtain 843.53mg of a crude product.

To the crude product obtained, ethanol (30mL) and water (2.6mL) were added. The resulting solution was stirred at 97 ℃ for 25 minutes and cooled to 25 ℃ at a rate of about 1 ℃/min. The solution was stirred at about 25 ℃ for 30 minutes and under ice-cooling conditions for 1 hour to obtain a precipitate. The precipitate was collected by filtration, washed twice with ethanol (3mL) and dried at 50 ℃. The mother liquor was concentrated under reduced pressure and dried at 50 ℃.

The product (569.2mg,47mCi,82.6 μ Ci/mg) was collected by filtration and the concentrated mother liquor (228.3mg,17.9mCi,78.4 μ Ci/mg) and compound D (383.8mg) were combined using ethanol (42mL) and water (3.6 mL). The resulting mixture was stirred at 80 ℃ under nitrogen atmosphere until the solid was completely dissolved. Gradually cooling the mixed solution to 39-40 ℃ at the speed of 1 ℃/min. The mixture was kept at 39 ℃ for 30 minutes and then gradually cooled to 23 ℃ at a rate of 1 ℃/min. The mixture was kept at room temperature for 30 minutes and then kept under ice-cooling for 45 minutes to obtain a precipitate. The precipitate was collected by filtration and washed twice with ethanol (3mL) to obtain a white solid. The white solid was dried under reduced pressure to obtain compound C.

ESIMS (Positive ion mode) M/z:440(M + H)⁺,442(M+H)⁺

[ reference example 4]7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl]-6-fluoro-1- (2-) Fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid hydrochloride (Compound D)

7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid hydrochloride (Compound D) was synthesized according to the procedure of example 1 in patent document 2. The amount of compound D described in the following test examples is a value converted into a free form.

[ test example 1] concentration in tissue (rat, oral administration)

Compound C (10.83mg/kg) (solvent: water) was orally administered to SD rats in a single dose under fasting conditions. Lung tissue and plasma were collected 1, 6 and 24 hours after dosing. Lung tissue was dried and treated with a sample oxidant system (sample oxidant: model 307, PerkinElmer, glass vial: 20mL, Wheaton Industries, carbon dioxide absorbent: Carbo-Sorb 8mL, PerkinElmer, scintillation cocktail (シンチレ - シヨンカクテル): Permafluor 12 mL, PerkinElmer) and the radioactive concentration was measured. The plasma was fractionated in ミディ vials (8mL, PerkinElmer), 6mL scintillation cocktail (UltimaGold) was added, and the radioactive concentration was measured. The radioactivity concentration (mean, n-3) was measured using a liquid scintillation counter (Tri-Carb 2500TR or 2700TR, PerkinElmer).

The results are shown in table 1.

[ Table 1]

Tissue distribution rate represents the value obtained by dividing the radioactive concentration in lung tissue by the radioactive concentration in plasma.

As can be seen from table 1, compound C rapidly distributed into lung tissue after administration, and the tissue distribution rate into lung was very high, reaching "3.7", 1 hour after administration.

This value is higher than that of commercially available quinolone formulations such as "2.7" for sitafloxacin (tissue distribution rate into lung tissue of male rats 0.5 hour after single oral administration) ("インタビユ - フオ - ム from グレ - スビツト (registered trademark) 50mg tablet and グレ - スビツト (registered trademark) 10% granule), and" 2.7 "for ofloxacin (tissue distribution rate into lung tissue of rats 1.0 hour after oral administration) (インタビユ - フオ - ム from タリビッド (registered trademark) 100mg tablet).

[ test example 2] concentration in tissue (human, oral administration)

The method in the reference (antibacterial Agents and Chemotherapy, 2.2010, page 866-870) measures the concentration of the drug in lung tissue (alveolar epithelial lining and alveolar macrophages) and in plasma after a single oral administration of compound D to investigate the intrapulmonary distribution of compound D.

The measurement was performed as follows. Compound D (75mg) was administered orally in a single dose to healthy adult male volunteers. Bronchoalveolar lavage fluid and blood samples were collected from the subjects at 1, 2,4, 6, and 24 hours after administration. Lavage and blood samples were collected at each time point for six subjects. Bronchoalveolar lavage fluid was centrifuged to separate from alveolar epithelial lining fluid and alveolar macrophages for measurement of drug concentration. The concentration of compound D in lung tissue and plasma was measured by LC/MS. The mean ratio of lung tissue concentration to plasma concentration at each sampling (time) point is shown in table 2 as the tissue distribution rate.

[ Table 2]

As shown in Table 2, the tissue distribution rates of Compound D in alveolar epithelial lining fluid and alveolar macrophages were extremely high, ranging from 15.0 to 22.5 and from 18.5 to 56.4, respectively. Compound D can reach respiratory organ infection foci at high concentrations and shows strong antibacterial action against target pathogens causing respiratory tract infections. It is therefore suggested that compound D is particularly excellent for the treatment of respiratory tract infections.

In addition, the tissue distribution rates of compound D in alveolar epithelial lining fluid and alveolar macrophages 1 hour after administration were 22.5 and 31.9, respectively, which showed significantly good distribution. The initial antimicrobial effect after infection is important for the treatment of respiratory infections. Compound D rapidly distributed to the lung infected foci 1 hour after administration. Thus, compound D is particularly useful for treating respiratory tract infections.

The tissue distribution rate of levofloxacin in human bronchoalveolar lavage fluid is 1.1-3.0 (0.5-8 hours after administration), and the tissue distribution rate in alveolar macrophages is 4.1-18.9 (0.5-24 hours after administration) (インタビユ - フオ - ム from クラビット (registered trademark) 250mg and 500mg tablets, and クラビット (registered trademark) 10% granules). The tissue distribution rate of gatifloxacin in human alveolar epithelial lining fluid was 0.95 ± 0.41 (2.5 to 3.5 hours after administration) and 11.15 ± 8.16 (2.5 to 3.5 hours after administration) (イン th ビユーフオーム from ジエニナツク (registered trademark) 200mg tablet). The tissue distribution rate of moxifloxacin in human airway secretions was 6.78 (3 hours post-administration) and the tissue distribution rate in alveolar macrophages was 18.59 (3 hours post-administration) (インタビユ - フオ - ム from アベ oral ツクス (registered trademark) 400mg tablets). These data indicate that the tissue distribution rate of compound D is significantly higher compared to the commercial quinolone.

Advantageously, the high distribution rate of lung tissue is expected to provide high clinical efficacy using small doses. Due to this property, the daily dose can be set lower compared to other quinolone compounds. It is suggested that side effects may be reduced.

Due to the high distribution rate into lung tissue, compound D can provide high concentrations in respiratory organ infection foci and can cause prevention of the emergence of antibacterial resistant bacteria.

These advantages contribute to the efficacy of 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof for respiratory infections.

It is understood that an infection therapeutic agent containing 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof can be constructed, and in the case of administration to a human, the compound has a tissue distribution rate into the alveolar epithelial lining fluid 1 hour after administration of 10 or more. The tissue distribution rate into the alveolar epithelium lining fluid 1 hour after administration is preferably in the range of 10 to 50, and more preferably 15 to 40.

[ test example 3] enzyme inhibitory Activity of Streptococcus pneumoniae

According to animicrob. ingredients chemither.47: 77-81(2003), measuring the inhibitory activity of Compound D against DNA gyrase derived from Streptococcus pneumoniae IID553, based on the amount of supercoiled form DNA produced using relaxed pBR322 as a substrate. The inhibitory activity of compound D against topoisomerase IV was measured based on the amount of production of the unlinked form of DNA using kinetoclast DNA as a substrate. Similarly, the inhibitory activity of Levofloxacin (LVFX) and Ganofloxacin (GRNX) was measured. The results are compared. The results are shown in table 3. 50% Inhibitory Concentration (IC) in Table 3₅₀) Values represent the mean ± SD of three measurements.

[ Table 3]

It can be seen that compound D is superior to levofloxacin and carnofloxacin in terms of inhibitory activity against the enzyme derived from streptococcus pneumoniae.

[ test example 4] antibacterial Activity against quinolone-resistant Strain (in vitro)

The in vitro antibacterial activity of compound D, levofloxacin, ganofloxacin and Ciprofloxacin (CPFX) against quinolone-resistant strains of streptococcus pneumoniae was measured according to the Clinical and Laboratory Standards Institute (CLSI) microdilution method. The results are shown in table 4.

[ Table 4]

In Table 4, strain No.1 is a quinolone intolerant strain (parent strain), and strains No.2 to 7 are quinolone resistant strains. As seen from the results, compound D also maintained excellent activity against quinolone-resistant strains compared to other quinolone compounds. In particular, compound D exhibited high activity against the No.6 strain (streptococcus pneumoniae ST9941) and the No.7 strain (streptococcus pneumoniae SN9981), which are double mutant strains, compared to other quinolone compounds.

[ test example 5] antibacterial Activity against Streptococcus pneumoniae (in vitro)

The in vitro antibacterial activity of compound D, ganofloxacin and levofloxacin against strains in mice infected with streptococcus pneumoniae (streptococcus pneumoniae KY-9) was measured according to the CLSI microdilution method. The results are shown in table 5.

[ Table 5]

[ test example 6] number of bacteria in Lung

At 7.4X 10⁵CFU/mouse streptococcus pneumoniae KY-9 was inoculated via the respiratory tract into the lungs of mice to which cyclophosphamide had been administered. 2.9-3.1 hours, 17.3-19.1 hours, and 24.4-26.1 hours post inoculation, for a total of three Subcutaneous (SC) or oral (PO) administrations (Compound D, levofloxacin or Ganofloxacin). The number of bacteria in the lungs was measured 16.5-17.0 hours after the final dosing. The results are shown in figures 1 and 2.

The ".") depicted in fig. 1 and 2 indicates that significant differences were observed in the vehicle group (p <0.05) and the "-" indicates that significant differences were observed in the vehicle group (p <0.001) (dunnett multiple comparison test, parametric test).

As can be seen from figure 1, a significant dose-dependent reduction in the number of bacteria in the lung was observed following subcutaneous administration of compound D (6.3mg and 25 mg/kg). After subcutaneous administration of 6.3mg/kg of gatifloxacin, no significant reduction in the number of bacteria in the lungs was observed. However, when the dose of garenoxacin was increased to 25mg/kg, a significant reduction in the number of bacteria in the lungs was observed. Herein, CFU is an abbreviation for colony forming unit and represents a unit of bacterial number. Log CFU/lung represents the number of viable bacteria in the lung. Log CFU/lung was determined as follows. Lungs obtained from mice were homogenized to obtain bacterial cultures. The bacterial culture was appropriately diluted, applied to an agar plate medium, and cultured. Log CFU/lung was determined based on the number of colonies developed.

The therapeutic effects of compound D and garenoxacin were compared in the 25mg/kg administration group. Number of viable bacteria in lungs was 10 for compound D^2.6CFU/Lung, number 10 for Carnoxacin^5.5CFU/lung. About a 1,000 fold difference was observed. The Minimum Inhibitory Concentration (MIC) of compound D against streptococcus pneumoniae (streptococcus pneumoniae KY-9) was comparable to that of ganaxacin (see table 5), but compound D had excellent tissue distribution into the lungs, exerting a higher therapeutic effect than ganaxacin.

For levofloxacin, no significant reduction in the number of bacteria in the lung was found even after subcutaneous administration of 100 mg/kg.

Fig. 2 is a graph showing the number of bacteria in the lungs after oral administration. Similar to subcutaneous administration, the therapeutic effect of compound D was superior compared to that of ganofloxacin and levofloxacin.

As seen from test examples 3 to 6, it can be understood that compound D has an excellent effect on Streptococcus pneumoniae, and that compound D is effective as a therapeutic agent for diseases in which the pathogenic bacterium is Streptococcus pneumoniae. Examples of diseases in which the pathogenic bacterium is streptococcus pneumoniae may include otorhinolaryngological diseases such as sinusitis and otitis media, in addition to respiratory organ infections such as pharyngitis, laryngitis, tonsillitis, acute bronchitis, pneumonia and secondary infections of chronic respiratory organ diseases.

Thus, as an aspect of the present invention, there can be exemplified a therapeutic agent for an infection which is one or two or more selected from the group consisting of: pharyngitis, laryngitis, tonsillitis, acute bronchitis, pneumonia, secondary infection of respiratory diseases, sinusitis and otitis media, which comprises 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof as an active ingredient.

[ test example 7] antibacterial Activity against clinically isolated strains (in vitro)

The in vitro antibacterial activity of compound D, ganofloxacin and levofloxacin against each of the clinically isolated strains of streptococcus pneumoniae, moraxella catarrhalis and haemophilus influenzae was measured according to the CLSI microdilution method or the CLSI agar dilution method. MIC₉₀The value is the minimum concentration at which 90% of the growth of the strains was inhibited for all measured strains. The results are shown in table 6.

[ Table 6]

¹⁾PSSP represents penicillin-resistant Streptococcus pneumoniae.

²⁾Ampicillin insensitive strains: 7 strains;

ampicillin sensitive strains: 19 strains;

³⁾ampicillin insensitive strains: 2 strains;

ampicillin sensitive strains: 24 strains

[ test example 8] AUC and Cmax

6 Japanese healthy adult males received an oral dose of 75mg of Compound D once daily for 7 consecutive days. Plasma concentrations of compound D were measured by HPLC method and pharmacokinetic parameters were calculated.

The maximum drug concentration (Cmax) value and area under the curve (AUC) at day 7 were 0.998. mu.g/mL and 20.6. mu.g-h/mL, respectively. These values are very low compared to either ganoxacin or levofloxacin. After continuous administration of gatifloxacin at a daily dose of 400mg, Cmax was 11.06 μ g/mL and AUC was 110.9 μ g-h/mL (hei chemie of japan: 35468, volume 55, phase S-1, pages 95-115). Cmax was 6.32 μ g/mL and AUC was 49.67 μ g.h/mL after continuous levofloxacin administration at a daily dose of 500mg (hei chemi hei 35468, volume 57, phase S-2, pages 1-10).

[ test example 9] clinical efficacy

We investigated the efficacy of compound D for patients with community-acquired pneumonia. 75mg of compound D was orally administered to 50 patients with community-acquired pneumonia once a day for 7 days. Clinical efficacy (cure rate) was evaluated 7 days after the completion of treatment. Clinical tests were conducted on the part of patients suffering from community-acquired pneumonia (pages 34 to 38) evaluated by "anti-bacterialism medicine bed value method for preventing and treating respiratory infection における (second edition).

The clinical efficacy (cure rate) of compound D was 90.0%. The effective rate is no less than those of ganofloxacin and levofloxacin.

In a clinical trial with 400mg of gatifloxacin for patients with bacterial pneumonia, the clinical effective rate is 94.9% (hei 35468, volume 55, No. s-1, page 127-142, japan chemical association. In a clinical trial with 500mg levofloxacin for patients with community-acquired pneumonia, secondary bacterial respiratory organ infection of chronic respiratory organ disease, and acute bronchitis, the clinical efficacy was 89.3% (hei chemie association, No. 35468, No. s-2, page 20-32.

From the results of test examples 7 to 9, the MIC of Compound D was not lower than that of Ganoxacin and levofloxacin (test example 7). Although the concentration of compound D in plasma is low (see test example 8), compound D shows high therapeutic efficacy similar to that of ganofloxacin and levofloxacin used for treating respiratory tract infection (test example 9).

As shown in table 2, compound D has a very excellent distribution into human lung tissue. Thus, compound D may show high therapeutic efficacy even at low plasma concentrations. Unlike other drugs, compound D does not require high plasma concentrations. For this reason, the dose of compound D can be reduced, and reduction of side effects can be expected, and the formulation is miniaturized so that it can be easily administered.

Test example 10 frequency of development of drug-resistant bacteria

The frequency of development of compound D, levofloxacin, ganaxacin and ciprofloxacin resistant bacteria was investigated against staphylococcus aureus ATCC29213, streptococcus pneumoniae ATCC49619 and escherichia coli ATCC 25922. The frequency of development of drug-resistant bacteria during about 70 hours of strain culture in the presence of drugs at concentrations 4, 8 and 16 times (4 × MIC, 8 × MIC and 16 × MIC) the MIC value of each strain was investigated.

Staphylococcus aureus ATCC29213 is Staphylococcus aureus, Streptococcus pneumoniae ATCC49619 is Streptococcus pneumoniae, and Escherichia coli ATCC25922 is Escherichia coli. Escherichia coli is known as a major causative microorganism of chronic respiratory tract infection.

The frequency of development of drug-resistant bacteria was calculated by: the number of colonies developed on agar medium with each drug concentration was divided by the number of bacteria initially inoculated.

The results are shown in table 7.

[ Table 7]

The culture time was 70 hours and 50 minutes for Staphylococcus aureus and Escherichia coli, and 69 hours for Streptococcus pneumoniae.

In table 7, it is shown that resistant bacteria were developed.

For all three bacteria that have been evaluated, no development of compound D-resistant bacteria was observed.

On the other hand, levofloxacin-resistant bacteria were developed against escherichia coli ATCC25922, and carnofloxacin-resistant bacteria were developed against staphylococcus aureus ATCC 29213. Ciprofloxacin-resistant bacteria were developed against all three bacteria.

The results suggest that it is less likely to develop a bacterium resistant to compound D than other quinolone compounds.

[ test example 11] enzyme inhibitory Activity against Staphylococcus aureus

The inhibitory activity of compound D against DNA gyrase obtained from Staphylococcus aureus and quinolone-resistant Staphylococcus aureus was measured based on the amount of production of supercoiled form DNA using relaxed pBR322 as a substrate according to Antiicrob. Agents Chemother.45:3544-3547 (2001). The inhibitory activity of compound D against topoisomerase IV was measured based on the amount of production of the unlinked form of DNA using kinetoclast DNA as a substrate. The measurement was carried out in the same manner as in test example 3. Similarly, the inhibitory activity of ciprofloxacin, levofloxacin and ganofloxacin was measured. The results are compared.

The results are shown in tables 8 to 9.

[ Table 8]

IC₅₀The value: mean or mean of three measurements. + -. SD

[ Table 9]

IC₅₀The value: mean of three measurements. + -. SD

As understood from tables 8 and 9, the inhibitory effects of compound D against DNA gyrase and topoisomerase IV obtained from staphylococcus aureus were higher than those of the other compounds, regardless of whether each enzyme was obtained from a quinolone-resistant strain.

Comparison of the inhibitory effect on the enzymes obtained from the non-quinolone-resistant strains with the inhibitory effect on the enzymes obtained from the quinolone-resistant strains suggests that the inhibitory activity of compound D against these enzymes is less likely to be affected by quinolone-resistant mutations than other compounds.

[ test example 12] antibacterial Activity against quinolone-resistant Strain (in vitro)

The in vitro antibacterial activity of compound D, levofloxacin, ganaxacin and ciprofloxacin against quinolone-resistant strains of streptococcus pneumoniae was measured according to the CLSI agar microdilution method or the CLSI microdilution method.

The results are shown in table 10.

[ Table 10]

As seen from table 10, compound D retained excellent activity against the quinolone-resistant strain in addition to the parent strain (quinolone-intolerant strain) compared to other quinolone compounds. It was observed that the MIC of compound D against highly quinolone-resistant Staphylococcus aureus (step 4 grlA, gyrA, grlA, gyrA four mutant strains) was 2. mu.g/mL, and the potency (action strength) was 16-fold or more higher than that of other quinolone compounds.

Industrial applicability

This embodiment can provide a novel therapeutic agent for respiratory organ infection, which contains 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] 6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof, and which is industrially useful.

Claims

Use of 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a respiratory infection in humans, wherein the pathogenic bacterium responsible for said respiratory infection is selected from the group consisting of bacteria belonging to Moraxella catarrhalis and Haemophilus influenzae, and wherein 7- [ (3S,4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, the daily dose of 4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof is 10mg or more and 250mg or less.
2. Use according to claim 1, wherein the respiratory organ infection is one or two or more infections selected from: pharyngitis, laryngitis, tonsillitis, acute bronchitis, pneumonia and secondary infection of chronic respiratory diseases.